This invention is directed to compounds of the formula I described herein, to a pharmaceutical composition comprising such compounds and to methods of preventing or treating disorders or conditions that may be treated by administration of such compounds to a mammal in need, including humans. In particular, the compounds of the current invention are potentially useful for treating certain protozoal infections including, for example, human African trypanosomiasis (HAT) and Chagas disease.
Human African Trypanosomiasis (HAT) is a disease spread by a parasitic organism, trypanosoma brucei, which is transmitted to humans primarily via bites from the tsetse fly—transmission may also occur via blood transfusion or in utero exposure of a fetus from an infected mother via the placenta. It is often referred to as “sleeping sickness” because of the symptoms that develop in patients who have progressed to the advanced, or Stage 2, level of infection wherein the parasite has passed the blood brain barrier (BBB) exposing the central nervous system (CNS) of the victim to further infection by the parasite. Left untreated, this latter stage of the disease is typically fatal. Jacobs and Ding, Annual Reports in Medicinal Chemistry, 2010-45, 277-294; Chapter 50 of Goodman and Gilman's, The Pharmacological Basis of Therapeutics, 12th Ed., 2011, 1419-1441.
The disease is found in two forms, depending on the parasite sub-species involved, either Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. Humans are the primary host for Trypanosoma brucei gambiense, whereas wild game animals and cattle are the primary target of T. b. rhodesiense. T. b. gambiense is found in central and western Africa and causes a chronic condition that can remain in a passive phase for months or years before symptoms emerge. T. b. rhodesiense is found in southern and eastern Africa; symptoms of infection by T. b. rhodesiense generally emerge in a few weeks and are more virulent and faster developing than T. b. gambiense. 
While approximately one-half million inhabitants of sub-Saharan Africa are potentially infected each year by the hemolymphatic, Stage 1, form of HAT. The number of HAT cases has been diminishing, with the WHO estimating an annual mortality of 10,000 (see P. P. Simarro, et al, International Journal of Health Geographics, 2010, 9, 57). However, this trend has varied over the years and, with few efficacious and cost effective preventative measures being consistently used, the number of cases would quickly rebound. Symptoms include fever, headaches, joint pains and itching, as well as severe swelling of lymph nodes. Chronically, HAT can produce more extensive symptoms including anemia, endocrine, cardiac and kidney dysfunctions.
The drugs that are available act directly on the invasive protozoa in the bloodstream; penetration of the blood-brain barrier (BBB) has limited the use of some of these drugs to treatment of the hemolymphatic, first stage of HAT. These include suramin, developed in the 1920's and primarily used for Stage 1 T. b. rhodesiense HAT; pentamidine, discovered in 1940, which requires multiple intramuscular (i.m.) injections and is only effective for Stage 1 HAT; melarsoprol (identified in 1949) which also requires multiple, painful daily injections and is highly toxic, often used for the most severely ill Stage 2 patients; and eflornithine, a drug developed in 1981 which requires slow i.v. infusions over a two-week period to ensure sufficient CNS exposure to treat T. b. gambiense-induced Stage 2 HAT. A nifurtimox-eflornithine combination therapy (NECT) was created in 2009; it appears to be better tolerated for Stage 2 HAT patients (see Nok, Expert Opinion in Pharmacotherapy, 2005, 6(15), 2645-2653).
Of growing concern in recent years is the issue of cross-resistance to some of these medications. This has been observed with pentamidine and arsenicals like melarsoprol. (See de Koning, Trends in Parasitology, 2008, 24(8), 345-349).
Interestingly, the organism that is responsible for HAT, T. brucei, is related to other parasitic species that can cause severely debilitating diseases in humans and animals. Chagas disease, caused by the related parasite T. cruzi, is prevalent in South America, affecting up to 10 million individuals and has also been detected in cattle; fatalities from Chagas are estimated to be about 21,000 per year. Leishmaniases, in their various manifestations—cutaneous Leishmaniasis (via L. major, L. mexicana, L. aethiopica, L. tropica), mucocutaneous leishmaniasis (L. braziliensis) and visceral leishmaniasis (L. donovani/infantum) are estimated to affect nearly 2 million people on four continents. It is quite possible that any new treatment for HAT which targets the T. brucei parasite could have sufficient efficacy against these related parasitic species and, therefore would be a valuable improvement in antiparasitic therapy. (See Silva, et al, Biochemical Pharmacology, 2007, 73, 1939-1946).
One of the most commonly used HAT treatments for Stage 1 is pentamidine. This diamidine compound has been extensively studied with respect to structure-activity relative to the replacement of its 1,5-dioxopentyl section by a variety of aryl and heteroaryl rings (See, e.g., R. R. Tidwell, et al, in Journal of Medicinal Chemistry, 2006, 49, 5324; Journal of Medicinal Chemistry, 2007, 50, 2468; Journal of Medicinal Chemistry, 2008, 51, 6923; Journal of Medicinal Chemistry, 2009, 52, 5763; Journal of Medicinal Chemistry, 2010, 53, 254). Little research has been done to enhance pentamidine's brain concentration through the incorporation into the molecule of CNS-penetration enhancing groups, such as those found in some effective antipsychotic and antidepressant drugs currently on the market.
Malaria is another infectious disease caused by parasitic protozoa. Transmitted via a bite from an infected female Anopheles mosquito into a human or animal's circulatory system, they travel to the liver to mature and reproduce. Malaria causes symptoms that typically include fever and headache, which in severe cases can progress to coma or death. The disease is widespread in tropical and subtropical regions in a broad band around the equator, including much of Sub-Saharan Africa, Asia, and the Americas. Five species of Plasmodium can infect and be transmitted by humans; the vast majority of deaths are caused by P. falciparum and P. vivax. 
Symptoms of falciparium malaria appear 9-30 days after infection (Bartoloni A, Zammarchi L (2012). “Clinical aspects of uncomplicated and severe malaria”. Mediterranean Journal of Hematology and Infectious Diseases 4 (1): e2012026). Individuals with cerebral malaria frequently exhibit neurological symptoms, including abnormal posturing, nystagmus, conjugate gaze palsy (failure of the eyes to turn together in the same direction), opisthotonus, seizures or coma. Serious complications of malaria include the development of respiratory distress, which occurs in up to 25% of adults and 40% of children with severe P. falciparum malaria. Infection with P. falciparum may result in cerebral malaria, a form of severe malaria that involves encephalopathy.
The World Health Organization (WHO) estimated that in 2010, there were 219 million documented cases of malaria and 1.24 million deaths (Murray C J, Rosenfeld L C, Lim S S, Andrews K G, Foreman K J, Haring D, Fullman N, Naghavi M, Lozano R, Lopez A D (2012). “Global malaria mortality between 1980 and 2010: A systematic analysis”. Lancet 379 (9814): 413-31). The majority of cases (65%) occur in children under 15 years old and maternal malaria is associated with up to 200,000 estimated infant deaths yearly (Hartman T K, Rogerson S J, Fischer P R (2010). “The impact of maternal malaria on newborns”. Annals of Tropical Paediatrics 30 (4): 271-82).
Several medications are available to prevent malaria in travelers to malaria-endemic countries. Severe malaria is treated with intravenous or intramuscular quinine or, since the mid-2000s, the artemisinin derivative artesunate, which is superior to quinine in both children and adults and is given in combination with a second anti-malarial such as mefloquine. Resistance has developed to several antimalarial drugs; for example, chloroquine-resistant P. falciparum has spread to most malarial areas, and emerging resistance to artemisinin has become a problem in some parts of Southeast Asia.
Uncomplicated malaria may be treated with oral medications. The most effective treatment for P. falciparum infection is the use of artemisinins in combination with other antimalarials known as artemisinin-combination therapy (or ACT), which decreases resistance to any single drug component (Kokwaro G (2009). “Ongoing challenges in the management of malaria”. Malaria Journal 8 (Suppl. 1): S2). These additional antimalarials include: amodiaquine, lumefantrine, mefloquine or sulfadoxine/pyrimethamine. Another recommended combination is dihydroartemisinin and piperaquine (WHO 2010, pp. 75-86; Kokwaro G (2009) “Ongoing challenges in the management of malaria”. Malaria Journal 8 (Suppl. 1): S2).
There are a number of drugs that can help prevent malaria while travelling in areas where it exists. Most of these drugs are also sometimes used in treatment. Chloroquine may be used where the parasite is still sensitive (Jacquerioz F A, Croft A M (2009). “Drugs for preventing malaria in travelers”. In Jacquerioz F A. Cochrane Database of Systematic Reviews (Online) (4): CD006491). Because most Plasmodium is resistant to one or more medications, one of three medications—mefloquine, doxycycline or the combination of atovaquone and proguanil hydrochloride—is frequently needed. Doxycycline and the atovaquone and proguanil combination are the best tolerated; mefloquine is associated with death, suicide, and neurological and psychiatric symptoms. The protective effect does not begin immediately, and people visiting areas where malaria exists usually start taking the drugs one to two weeks before arriving and continue taking them for four weeks after leaving (with the exception of atovaquone/proguanil, which only needs to be started two days before and continued for seven days afterward) (Freedman DO (2008). “Clinical practice. Malaria prevention in short-term travelers”. New England Journal of Medicine 359 (6): 603-12.
Aromatic amidine compounds have been reported to have efficacy in the treatment of human and animal disorders like giardiasis (U.S. Pat. No. 4,963,589, issued Oct. 16, 1990), pneumocystis carinii pneumonia (U.S. Pat. No. 4,933,347, issued Jun. 12, 1990), leishmania donovani (U.S. Pat. No. 5,786,383, issued Jul. 28, 1998), plasmodium falciparum malaria (U.S. Pat. No. 5,206,236, issued Apr. 27, 1993), as well as their use as anticoagulants (U.S. Pat. No. 5,866,577, issued Feb. 2, 1999), antiproliferative agents (U.S. Pat. No. 6,699,862, issued Mar. 2, 2004) and antihistamine substances (U.S. Pat. No. 4,748,165, issued May 31, 1988)